MicroRNAs (miRNAs) control protein output in development and cancer. The let-7 miRNA family members act as tumor suppressors by negatively regulating the translation of oncogenes. The RNA-binding proteins Lin28a and Lin28b block the processing of all let-7 members and promote tumor progression. Lin28a overexpression in mice leads to overgrowth and metabolic alterations, including increased glucose uptake, increased insulin sensitivity, and decreased mitochondrial gene expression. Since this metabolic state is observed in cancer, Dr. Zhu hypothesized that these developmental functions for Lin28a are especially relevant in cancer. Indeed, LIN28A and LIN28B are overexpressed in human sarcomas and cell lines, and the Lin28a Tg mice develop an array of soft-tissue tumors. Dr. Zhu will test the hypothesis that the Lin28/let-7 pathway drives growth and metabolic changes in sarcoma. Specifically, this proposal will aim to: 1. Define the role of the Lin28/let-7 pathway in this mouse model of sarcoma, 2. Dissect the mechanism by which Lin28 and let-7 regulate metabolism in sarcoma and muscle and 3. Determine how interactions between the Lin28, Igf2bp and Hmga gene families affect growth and metabolism in sarcoma. When completed under the auspices of a K08 award, this project will define how miRNAs and their regulators can influence metabolism, and could have therapeutic implications in a broad array of neoplastic and metabolic diseases. Dr. Zhu is a clinical oncology fellow at Dana-Farber Cancer Institute (DFCI) and his proposed 5-year mentored research plan will be performed in the laboratory of Dr. George Daley in the Division of Hematology/Oncology at Children's Hospital Boston (CHB). Dr. Zhu's background is in embryology and stem cell biology, and his long-term career goal is to integrate his scientific and clinical expertise to investigate metabolic and developmental mechanisms in clinically relevant cancer models. Under the mentorship of Dr. Daley, a leader in cancer modeling and stem cell biology, Dr. Zhu has developed a research and training platform that will equip him with the intellectual skills and experimental approaches necessary to be productive in both a mentored and independent setting. To accomplish this, Dr. Zhu will take advantage of the expertise and resources of the Daley Lab, obtain formal training in metabolism and metabolomic analysis, establish collaboration and consultation with a team of experts, and acquire a relevant fund of knowledge through local and international meetings. The plan will be carried out in the Division of Hematology/Oncology at CHB, a rich and proven environment for training physician-scientists. PUBLIC HEALTH RELEVANCE: Sarcoma represents both a clinical challenge, given their genetic diversity, and an opportunity, given the dramatic success of targeted molecular therapies in some sarcomas. LIN28A and LIN28B are cancer- promoting proteins that block the proper production of let-7;an important family of tumor suppressive microRNAs. Though LIN28A and B are expressed in a variety of human sarcomas, their roles in this context are undefined. Lin28a transgenic mice that we have developed in our lab display overgrowth, possess profoundly altered metabolism, and develop soft-tissue tumors. I will investigate the role of Lin28s and their microRNA target, let-7, in sarcoma development with a particular focus on analyzing how Lin28 causes metabolic changes in cancer. Since it is thought that cancer cells must re-structure their metabolism to gain a selective growth advantage, the Lin28 let-7 pathway could potentially be targeted to reverse the metabolic changes that are essential for cancer development.